Abstract
MicroRNAs (miRNAs), a class of endogenous small noncoding RNAs, mediate posttranscriptional regulation of protein-coding genes by binding to the 3′ untranslated region of target mRNAs, leading to translational inhibition, mRNA destabilization or degradation. A single miRNA concurrently down-regulates hundreds of target mRNAs, and thereby fine-tunes gene expression involved in diverse cellular functions, such as development, differentiation, proliferation, apoptosis and metabolism. However, it remains unknown whether the set of miRNA target genes designated “targetome” regulated by an individual miRNA constitutes the biological network of functionally-associated molecules or reflects a random set of functionally-independent genes. To address this question, we studied the molecular network of the whole human miRNA targetome. Among 1,223 human miRNAs derived from miRbase Release 16, Diana-microT 3.0, a target prediction program, predicted reliable targets from 273 miRNAs. Among them, KeyMolnet, a bioinformatics tool for analyzing molecular interactions on the comprehensive knowledgebase, successfully extracted molecular networks from 232 miRNAs. In miRNA targetome networks, the most relevant pathway was transcriptional regulation by RB/E2F, important regulators of oncogenic transformation, the disease was adult T cell lymphoma/leukemia, and the pathological event was cancer, indicating that the human miRNA system termed “miRNAome” plays a specialized role in regulation of oncogenesis. The predicted targets derived from approximately 20 % of all human miRNAs construct biologically meaningful molecular networks, supporting the view that the miRNA targetome generally constitutes the biological network of functionally-associated molecules in human cells.
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Abbreviations
- EMT:
-
Epithelial-mesenchymal transition
- HPRD:
-
Human protein reference database
- IPA:
-
Ingenuity pathways analysis
- KEGG:
-
Kyoto encyclopedia of genes and genomes
- miTG:
-
MicroRNA-targeted gene
- MRE:
-
MicroRNA recognition elements
- PPI:
-
Protein-protein interaction
- RISC:
-
RNA-induced silencing complex
- 3′ UTR:
-
3′ Untranslated region
References
Albert R, Jeong H, Barabasi AL (2000) Error and attack tolerance of complex networks. Nature 406:378–382
Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233
Bemis LT, Chen R, Amato CM et al (2008) MicroRNA-137 targets microphthalmia-associated transcription factor in melanoma cell lines. Cancer Res 68:1362–1368
Blenkiron C, Miska EA (2007) MiRNAs in cancer: approaches, aetiology, diagnostics and therapy. Hum Mol Genet 16 Spec No 1:R106–R113
Boominathan L (2010) The tumor suppressors p53, p63, and p73 are regulators of microRNA processing complex. PLoS One 5:e10615
Boross G, Orosz K, Farkas I (2009) Human microRNAs co-silence in well-separated groups and have different predicted essentialities. Bioinformatics 25:1063–1069
Boyle EI, Weng S, Gollub J et al (2004) GO::TermFinder–open source software for accessing gene ontology information and finding significantly enriched gene ontology terms associated with a list of genes. Bioinformatics 20:3710–3715
Calin GA, Sevignani C, Dumitru CD et al (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 101:2999–3004
Chung EY, Dews M, Cozma D et al (2008) c-Myb oncoprotein is an essential target of the dleu2 tumor suppressor microRNA cluster. Cancer Biol Ther 7:1758–1764
Cui Q, Yu Z, Pan Y et al (2007) MicroRNAs preferentially target the genes with high transcriptional regulation complexity. Biochem Biophys Res Commun 352:733–738
da Huang W, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4:44–57
Friedman RC, Farh KK, Burge CB et al (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105
Garzon R, Marcucci G, Croce CM (2010) Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov 9:775–789
Gregory PA, Bert AG, Paterson EL et al (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10:593–601
Guo H, Ingolia NT, Weissman JS et al (2010) Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466:835–840
Haflidadóttir BS, Bergsteinsdóttir K, Praetorius C et al (2010) miR-148 regulates Mitf in melanoma cells. PLoS One 5:e11574
Hsu CW, Juan HF, Huang HC (2008) Characterization of microRNA-regulated protein-protein interaction network. Proteomics 8:1975–1979
Hsu SD, Lin FM, Wu WY et al (2011) miRTarBase: a database curates experimentally validated microRNA-target interactions. Nucleic Acids Res 39:D163–D169
Johnson SM, Grosshans H, Shingara J et al (2005) RAS is regulated by the let-7 microRNA family. Cell 120:635–647
Kanehisa M, Goto S, Furumichi M et al (2010) KEGG for representation and analysis of molecular networks involving diseases and drugs. Nucleic Acids Res 38:D355–D360
Kitano H (2007) A robustness-based approach to systems-oriented drug design. Nat Rev Drug Discov 6:202–210
Liang H, Li WH (2007) MicroRNA regulation of human protein protein interaction network. RNA 13:1402–1408
Lu J, Getz G, Miska EA, Alvarez-Saavedra E et al (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838
Maragkakis M, Alexiou P, Papadopoulos GL et al (2009) Accurate microRNA target prediction correlates with protein repression levels. BMC Bioinformatics 10:295
O’Donnell KA, Wentzel EA, Zeller KI et al (2005) c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435:839–843
Petrocca F, Visone R, Onelli MR et al (2008) E2F1-regulated microRNAs impair TGFβ-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell 13:272–286
Place RF, Li LC, Pookot D et al (2008) MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci USA 105:1608–1613
Rivlin N, Brosh R, Oren M et al (2011) Mutations in the p53 tumor suppressor gene: important milestones at the various steps of tumorigenesis. Genes Cancer 2:466–474
Satoh J (2010) Bioinformatics approach to identifying molecular biomarkers and networks in multiple sclerosis. Clin Exp Neuroimmunol 1:127–140
Satoh J, Tabunoki H (2011) Comprehensive analysis of human microRNA target networks. BioData Min 4:17
Satoh J, Tabunoki H, Arima K (2009) Molecular network analysis suggests aberrant CREB-mediated gene regulation in the Alzheimer disease hippocampus. Dis Markers 27:239–252
Selbach M, Schwanhäusser B, Thierfelder N et al (2008) Widespread changes in protein synthesis induced by microRNAs. Nature 455:58–63
Shioya M, Obayashi S, Tabunoki H et al (2010) Aberrant microRNA expression in the brains of neurodegenerative diseases: miR-29a decreased in Alzheimer disease brains targets neurone navigator 3. Neuropathol Appl Neurobiol 36:320–330
Takamizawa J, Konishi H, Yanagisawa K et al (2004) Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 64:3753–3756
Tsang J, Zhu J, van Oudenaarden A (2007) MicroRNA-mediated feedback and feedforward loops are recurrent network motifs in mammals. Mol Cell 26:753–767
Tsang JS, Ebert MS, van Oudenaarden A (2010) Genome-wide dissection of microRNA functions and cotargeting networks using gene set signatures. Mol Cell 38:140–153
Vasudevan S, Tong Y, Steitz JA (2007) Switching from repression to activation: microRNAs can up-regulate translation. Science 318:1931–1934
Viswanathan GA, Seto J, Patil S et al (2008) Getting started in biological pathway construction and analysis. PLoS Comput Biol 4:e16
Volinia S, Galasso M, Costinean S et al (2010) Reprogramming of miRNA networks in cancer and leukemia. Genome Res 20:589–599
Wang WX, Huang Q, Hu Y et al (2011) Patterns of microRNA expression in normal and early Alzheimer’s disease human temporal cortex: white matter versus gray matter. Acta Neuropathol 121:193–205
Zhao H, Kalota A, Jin S et al (2009) The c-myb proto-oncogene and microRNA-15a comprise an active autoregulatory feedback loop in human hematopoietic cells. Blood 113:505–516
Acknowledgements
The author thanks Dr. Hiroko Tabunoki and Ms. Midori Ohta for their invaluable help. This work was supported by grants from the Research on Intractable Diseases (H21-Nanchi-Ippan-201; H22-Nanchi-Ippan-136), the Ministry of Health, Labour and Welfare (MHLW), Japan and the High-Tech Research Center Project (S0801043) and the Grant-in-Aid (C22500322), the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.
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Satoh, Ji. (2012). Human MicroRNA Targetome Indicates a Specialized Role of MicroRNAs in Regulation of Oncogenesis. In: Azmi, A.S. (eds) Systems Biology in Cancer Research and Drug Discovery. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4819-4_10
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DOI: https://doi.org/10.1007/978-94-007-4819-4_10
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